1. In a nutshell
Down Syndrome is a type of genetic disease, and is an example of an aneuploid condition. Down Syndrome typically results from an individual possessing an extra copy of chromosome 21 (trisomy 21). Clinical manifestations of Down Syndrome include abnormal facial features, cardiac defects, developmental delay and premature onset of significant cognitive decline. In the United States, Down Syndrome is thought to occur in around 1 in 700 live births; the risk of Down Syndrome increases exponentially with rising maternal age.
2. What causes it?
Molecular analysis has revealed that around 95% of individuals with Down Syndrome have an extra copy of chromosome 21. How the extra gene dosage contributes to the clinical features of Down Syndrome is poorly understood. Studies have revealed that approximately 75% of cases of trisomy 21 are caused by an additional maternal chromosome, and that a minority of Down Syndrome cases (~5%) are due to what is termed a robertsonian translocation. A translocation of this sort occurs when the long arm of chromosome 21 translocates to another acrocentric chromosome.
Figure 1. Trisomy 21 karyotype. Note the extra copy of chromosome 21. (Courtesy: National Human Genome Research Institute - Human Genome Project, Public Domain, https://commons.wikimedia.org/w/index.php?curid=889304)
3. What are the symptoms?
The range of phenotypic expression in Down Syndrome is extremely wide, and it is rare for any two individuals with the condition to exhibit the same set of clinical manifestations. Readily visible features of Down Syndrome include a flat facial profile, oblique palpberal fissures, and epicanthic folds. Congenital heart defects occur in approximately 50% of individuals with Down Syndrome. A leading cause of mental retardation, up to 80% of Down Syndrome patients have an IQ between 25 to 50. Alzheimer's-like neuropathic changes occur in virtually all affected individuals after the age of 40. Additionally, Down Syndrome patients have been observed to have defects in both cellular and humoral immune function, making them more susceptible to serious forms of infectious disease.
Figure 2. The clinical features and karyotypes of selected autosomal trisomies. (Kumar, 2020).
4. What’s going on?
The karyotype and clinical features of trisomy 21 have been known for decades. Despite this, the exact relationship between genotype and phenotype in Down Syndrome remains poorly understood. In trisomy 21, molecular analysis can show which gamete contributed the extra copy of chromosome 21. As there are no overt clinical differences between these types of trisomy 21 individuals, gametic imprinting is thought to play an insignificant role in the pathogenesis of Down Syndrome. A small subset of patients have 46 chromosomes, and Down Syndrome in these individuals is thought to occur due to robertsonian translocations that typically affect chromosomes 14 or 22; this type of genetic derangement is not associated with advanced maternal age, but can result in genetically unbalanced gamete cells - increasing the risk of recurrence. Karyotypic mosacism is observed in approximately 1% of Down Syndrome individuals and can occur both prezygotically and postzygotically. It is worth mentioning that mosaic individuals may have only mild phenotypic changes and a near normal IQ.
5. How is it treated?
Prenatal screening can be used to identify the condition before birth. Sometimes, the condition is suspected based on the appearance of the neonate, molecular analysis is used to confirm the clinical suspicion in these cases. In terms of management, early childhood intervention strategies, proper education and work-related training can improve the quality of life for individuals affected by Down Syndrome. Screening programs have improved the detection of congenital heart defects, and most serious cardiac malformations can be treated surgically. Hearing aids and speech therapy may benefit some individuals. The improved management of Down Syndrome has meant an increase in the longevity of affected individuals. The median age of death is now approximately 47 years, up from 25 years in 1983.
Figure 3. Enlarged NT and absent nasal bone in an eleven week old fetus with Down Syndrome. (This Photo was taken by Wolfgang Moroder)
6. That’s interesting...
Based on human and animal studies, the critical genetic loci involved in the pathogenesis of Down Syndrome is thought to involve genes that are involved in the normal function of the mitochondrial energy pathway, central nervous system development and folate metabolism.
